(1) Field of the Invention
The present invention relates to a method for simulating the functional attributes of human milk oligosaccharides in infants.
(2) Description of the Related Art
The infant gut microflora is rapidly established in the first few weeks following birth. The nature of this intestinal colonization is initially determined by early exposure to environmental sources of microbes as well as the health of the infant. Whether the infant is breast-fed or formula fed also has a strong influence on the intestinal bacterial population.
In the breast-fed infant, for example, Bifidobacterium spp. dominate among intestinal bacteria, with Streptococcus spp. and Lactobacillus spp. as less common contributors. In contrast, the microflora of formula-fed infants is more diverse, containing Bifidobacterium spp. and Bacteroides spp. as well as the more pathogenic species, Staphylococcus, Escherichia coli and Clostridia. The varied species of Bifidobacterium in the stools of breast-fed and formula-fed infants differ as well.
Bifidobacteria are generally considered “beneficial” bacteria and are known to protect against colonization by pathogenic bacteria. This likely occurs through competition for cell surface receptors, competition for essential nutrients, production of anti-microbial agents, and production of inhibitory compounds such as short chain fatty acids (SCFA) which may decrease fecal pH and inhibit potentially pathogenic bacteria. Bifidobacteria are also associated with resistance to gastrointestinal (GI) tract and respiratory infection as well as an enhanced immune function in children and infants. Therefore, the promotion of an intestinal environment in which Bifidobacteria dominate has become a goal in the development of nutritional formulations for formula-fed infants.
Human milk (HM) contains a number of factors that may contribute to the growth and population of Bifidobacteria in the gut microflora of infants. Among these factors is a complex mixture of more than 130 different oligosaccharides that reach levels as high as 8-12 g/L in transitional and mature milk. Kunz, et al., Oligosaccharides in Human Milk: Structure, Functional, and Metabolic Aspects, Ann. Rev. Nutr. 20: 699-722 (2000). These oligosaccharides are resistant to enzymatic digestion in the upper gastrointestinal tract and reach the colon intact, where they serve as substrates for colonic fermentation.
HM oligosaccharides are believed to elicit an increase in the number of Bifidobacteria in the colonic flora, along with a reduction in the number of potentially pathogenic bacteria. Kunz, et al., Oligosaccharides in Human Milk: Structure, Functional, and Metabolic Aspects, Ann. Rev. Nutr. 20: 699-722 (2000); Newburg, Do the Binding Properties of Oligosaccharides in Milk Protect Human Infants from Gastrointestinal Bacteria?, J. Nutr. 217:S980-S984 (1997). One way that HM oligosaccharides may increase the number of Bifidobacteria and reduce the number of potentially pathogenic bacteria is by acting as competitive receptors and inhibiting the binding of pathogens to the cell surface. Rivero-Urgell, et al., Oligosaccharides: Application in Infant Food, Early Hum. Dev. 65(S):43-52 (2001).
In addition to reducing the number of pathogenic bacteria and promoting the population of bifidobacteria, when HM oligosaccharides are fermented, they produce SCFAs such as acetic, propionic and butyric acids. These SCFAs are believed to contribute to caloric content, serve as a major energy source for the intestinal epithelium, stimulate sodium and water absorption in the colon, and enhance small bowel digestion and absorption. In addition, SCFA are believed to contribute to overall gastrointestinal health by modulating gastrointestinal development and immune function.
The fermentation of HM oligosaccharides also reduces fecal ammonia, amine, and phenol concentrations, which have been implicated as the major odorous components of feces. Cummings & Macfarlane, The Control and Consequences of Bacterial Fermentation in the Human Colon, J. Appl. Bacteriol. 70:443-459 (1991); Miner & Hazen, Ammonia and Amines: Components of Swine-Building Odor ASAE 12:772-774 (1969); Spoelstra, Origin of Objectionable Components in Piggery Wastes and the Possibility of Applying Indicator Components for Studying Odour Development, Agric. Environ. 5:241-260 (1980); O'Neill & Phillips, A Review of the Control of Odor Nuisance from Livestock Buildings: Part 3. Properties of the Odorous Substances which have been Identified in Livestock Wastes or in the Air Around them J. Agric. Eng. Res. 53:23-50 (1992).
As a result of the oligosaccharides present in HM, the SCFA profile of a breast-fed infant is very different from that of a formula-fed infant. For example, breast-fed infants produce virtually no butyrate, with acetate comprising approximately 96% of the total SCFA production. Lifschitz, et al., Characterization of Carbohydrate Fermentation in Feces of Formula-Fed and Breast-Fed Infants, Pediatr. Res. 27:165-169 (1990); Siigur, et al., Faecal Short-Chain Fatty Acids in Breast-Fed and Bottle-Fed Infants. Acta. Paediatr. 82:536-538 (1993); Edwards, et al., Faecal Short-Chain Fatty Acids in Breast-Fed and Formula-Fed Babies, Acta. Paediatr. 72:459-462 (1994); Parrett & Edwards, In Vitro Fermentation of Carbohydrates by Breast Fed and Formula Fed Infants, Arch. Dis. Child 76:249-253 (1997). In contrast, while formula-fed infants also have acetate (74%) as the major SCFA in feces, they have considerable amounts of propionate (23%) and small amounts of butyrate (3%) present as well. These differences between the SCFA profiles of breast-fed infants and formula-fed infants could affect the energy, digestion, and overall health of the formula-fed infant.
Because cow's milk and commercially available infant formulas that are based on cow's milk provide only trace amounts of oligosaccharides, prebiotics are often used to supplement the diet of formula-fed infants. Prebiotics have been defined as “non-digestible food ingredients that beneficially affect the host by selectively stimulating the growth and/or activity of one or a limited number of bacteria in the colon that can improve the health of the host”. Gibson, G. R. & Roberfroid, M. B., Dietary Modulation of the Human Colonic Microbiota-Introducing the Concept of Probiotics, J. Nutr. 125:1401-1412 (1995). Common prebiotics include fructo-oligosaccharide, gluco-oligosaccharide, galacto-oligosaccharide, isomalto-oligosaccharide, xylo-oligosaccharide and lactulose.
The incorporation of various prebiotic ingredients into infant formulas has been disclosed. For example, U.S. Patent App. No. 20030072865 to Bindels, et al. discloses an infant formula with an improved protein content and at least one prebiotic. The prebiotic component can be lacto-N-tetaose, lacto-N-fuco-pentaose, lactulose (LOS), lactosucrose, raffinose, galacto-oligosaccharide (GOS), fructo-oligosaccharide (FOS), oligosaccharides derived from soybean polysaccharides, mannose-based oligosaccharides, arabino-oligosaccharides, xylo-oligosaccharides, isomalto-oligo-saccharides, glucans, sialyl oligosaccharides, and fuco-oligosaccharides.
Similarly, U.S. Patent App. No. 20040191234 to Haschke discloses a method for enhancing the immune response which comprises administering at least one prebiotic. The prebiotic can be an oligosaccharide produced from glucose, galactose, xylose, maltose, sucrose, lactose, starch, xylan, hemicellulose, inulin, or a mixture thereof. The prebiotic can be present in an infant cereal.
Unfortunately, however, there are many disadvantages in the administration of the above prebiotics to formula-fed infants. While they may beneficially affect the population of probiotics in the gut, they do not produce a SCFA profile that is similar to that of a breast-fed infant. Additionally, the fermentation of many of these prebiotic substances occurs at a very rapid rate, which often produces excess gas, abdominal distension, bloating, and diarrhea. Therefore, the choice of prebiotic substances in infant formulas should be made with the goal of maximizing potential benefits and minimizing such unwanted side-effects.
Accordingly, it would be beneficial to provide a prebiotic substance that simulates the functional attributes of human milk oligosaccharides in infants, such as an increase in the population and species of beneficial bacteria in the infant gut and production of a SCFA profile similar to that of a breast-fed infant. Additionally, the prebiotic substance should be well tolerated in infants and should not produce or cause excess gas, abdominal distension, bloating or diarrhea.